tbuckley/cabot-search huggingface dataset:
Tracking C-type lectin-like receptor positive leukemic stem cells to determine therapeutic efficacy in acute myeloid leukemia.
Authors: Suhu Liu, Hong Lin, Fengshou Lan
Journal: Journal of Clinical Oncology (2022)

e19011 Background: Although the importance of leukemia stem cells (LSC) in disease course of acute myeloid leukemia (AML) is well established in basic research, detecting and tracking LSC is seldom adopted in routine clinical practice. This is partly due to difficulty in tracking LSC in routine clinical practice and the paucity of evidence to support the benefit of detecting LSC in guiding clinical practice. Recently, a functional LSC population has been methodically characterized immunophenotypically, and the C-type lectin-like receptor (CLL1; aka CD371) has been shown to be widely expressed on LSC but not on normal hematopoietic stem cells (HSC). We postulate that CLL1 can be used to track LSC in a clinical setting and by analyzing changes in the LSC Compartment, we may be better able to assess response to therapy. Methods: Bone marrow samples from non-M3 CD34+ AML patients that were positive for CLL1 expression were included. Flow cytometry data were retrospectively analyzed for CLL1 percent positivity in the HSC compartment, which was defined as the CD34 + CD38 low/- fraction. A chart review was conducted to determine correlation between CLL1 positive LSC compartment change and clinical outcome. Statistical analysis was performed using GraphPad Prism version 9. Results: From 12/2018 to 12/2021, 49 AML cases with both pre- and post-treatment data from a single institution, were identified for the study. Among them, fourteen patients with CLL1 positivity higher than 50% were analyzed for CLL1+/HSC fractional change between pre- and post-treatment. We found that 6 of these 14 patients with significant reduction in CLL1+/HSC achieved longer remission, while the other 8 patients with no significant decrease in the CLL1+/HSC fraction demonstrated no or only a temporary remission. Importantly, several cases of patients with significant reduction in CLL1 positive cells will be presented to highlight the fact that LSC fractional change was more accurate in evaluating therapeutic effects and more predictive of clinical outcome than traditional morphology and flow cytometric analysis. This may even alter interpretation of specific treatment outcomes by predicting, for example, the brief nature that can be expected from certain remissions. Lastly, the CLL1+/HSC compartment in the peripheral blood is highly correlated with that of the bone marrow, indicating future feasibility of tracking LSC fractional change non-invasively to guide therapeutic decisions. Conclusions: CLL1 as a LSC marker is readily applicable to the clinical setting. Tracking LSC before and after AML treatment provides critical information regarding therapeutic effects that can sometimes be missed by traditional morphological and flow cytometric analysis. Thus, measuring changes in the LSC compartment using CLL1 analysis should be incorporated routinely in clinical practice to guide therapy decisions.
Perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma (RAMSES/FLOT7) with high rate of signet cell component: Final results of the multicenter, randomized phase II/III trial of the German AIO and Italian GOIM.
Authors: Thorsten Oliver Goetze, Ralf-Dieter Hofheinz, Harald Schmalenberg, Dirk Strumberg, Eray Goekkurt, Stefan Angermeier, Thomas Zander, Jochem Potenberg, Hans-Georg Kopp, Daniel Pink, Gabriele Margareta Siegler, Michael Schenk, Ferdinando De Vita, Evaristo Maiello, Timo Gaiser, Disorn Sookthai, Tanita Brulin, Claudia Pauligk, Nils Homann, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2022)

4042 Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ type II and III (≥ cT2 or cN+) were enrolled. Pts were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) alone (Arm A) or the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, overall survival (OS), disease-free survival (DFS) and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 152 pts were analyzed within the intention to treat population. Baseline characteristics were similar between arms (male, 70%; median age, 60y; cT3/T4, 82%; cN+, 77%; GEJ, 45%). The rate of cancers with signet-ring cell component was at 45%. The FLOT-RAM arm included more unfavorable pts with T4 (8% vs. 5%), impaired ECOG PS of 1 (32% vs. 20%), and concomitant disease (86% vs. 76%). 92% of pts with FLOT as well as with FLOT-RAM completed the 4 pre- cycles. R0-resection could be achieved in 82% of pts with FLOT and 96% of pts with FLOT-RAM (p = 0.0093). The rate of major path response was similar in both arms and was 29% for FLOT and 26% for FLOT-RAM. Median DFS was slightly improved in pts with FLOT-RAM (32 months vs. 21 months), while median OS was similar in both treatment arms (FLOT 45 months, FLOT-RAM 46 months). Surgical morbidity was observed in 32% of pts with FLOT and 41% of pts with FLOT-RAM. Mortality at 60 days after surgery was 4.1% with FLOT and 2.8% with FLOT-RAM. There were bit more G≥3 adverse events with FLOT-RAM (76% vs. 92%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates and slightly prolonged DFS without an impact on path response or overall survival. FLOT-RAM is feasible and safe, when type I tumors are excluded. Clinical trial information: NCT02661971.
Lerociclib diminishes stemness in pediatric sarcoma cell lines.
Authors: Sara Hutchins, Laura V. Bownes, Colin H. Quinn, Janet R. Julson, Jerry E. Stewart, Jamie Aye, Karina J Yoon, Elizabeth A. Beierle
Journal: Journal of Clinical Oncology (2022)

e22010 Background: The outcomes for children with osteosarcoma and synovial sarcoma remain poor and are even worse for metastatic or relapsed disease. Those who do survive frequently suffer from long-term toxicities from current standard-of-care therapies. It is evident novel therapeutics are warranted to improve the outcomes for patients with these difficult tumors. Stem cell-like cancer cells (SCLCCs) are a subpopulation of tumor cells thought to be responsible for treatment resistance, development of metastases and tumor recurrence, making the targeting of this cell population critical. We sought to evaluate the effect of lerociclib, a CDK4/6 inhibitor, on pediatric sarcoma cell stemness. Methods: We investigated two established human osteosarcoma cells lines (U2-OS and MG-63), two metastatic synovial sarcoma patient-derived xenografts (PDXs) (COA-30 and COA-79) and a metastatic epithelioid sarcoma PDX (COA-171). Cells were treated with the CDK4/6 inhibitor, lerociclib, at concentrations below the known LD 50 . Synovial sarcoma stemness markers Octamer-binding transcription factor 4 (Oct4), homeobox protein Nanog, SOX 2 and nestin were evaluated by qPCR. CD117, a marker of stemness in osteosarcoma cells, was examined by flow cytometry. Finally, long-term passaged U2-OS and MG-63 cells were placed in low attachment serum-free conditions, and tumorsphere formation was evaluated using extreme limiting dilution assay (ELDA) in all cell lines. Results: Lerociclib treatment significantly decreased abundance of Oct4 (by 54%), Nanog (by 29%), SOX 2 (by 60%) and nestin (by 63%) mRNA in COA-30 synovial sarcoma cells. Cell surface expression of CD117 decreased from 17% to 11% in MG-63 cells when treated with lerociclib 2μM. Treatment of all cell types with lerociclib led to significantly decreased tumorsphere formation (Table). Conclusions: Treatment with lerociclib led to a decrease in mRNA abundance in known synovial sarcoma stem cell markers, a decrease in CD117 cell surface expression in osteosarcoma cells and decreased the ability of cells to form tumorspheres. These findings indicate lerociclib leads to decreased sarcoma cell stemness, which plays a key role in tumor progression and recurrence and should be further investigated for potential translation to the clinical setting.[Table: see text]
Selecting optimal timing of cranial radiotherapy-based on the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA) in patients with non-small cell lung cancer and brain metastases.
Authors: Xiaoyang Zhai, Ji Li, Wang Jing, Wenxiao Jia, Hui Zhu, Jinming Yu
Journal: Journal of Clinical Oncology (2022)

e21105 Background: The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA) index will provide more accurate prediction of expected survival for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). This retrospective study aims to evaluate optimal timing of cranial radiotherapy (RT) in NSCLC patients with BM stratified by Lung-molGPA index. Methods: This study retrospectively screened patients with NSCLC and initially diagnosed BM in our cancer center between February 2012 and July 2018. These enrolled patients were scored and stratified based on lung-molGPA index. The primary endpoint was overall survival time (OS), defined as the interval from the initiation of BM diagnosis to death caused by any reason or the last follow-up. And the secondary endpoint was progression free survival (PFS), referred to the interval from the initiation of BM diagnosis to disease progression or death caused by any reason. The effect of radiotherapy timing on survival time in groups stratified by lung-molGPA index was evaluated. The early RT was defined as receiving RT within three months after initial diagnosis of BM with no progression of BM prior to RT. And the delayed RT was defined as receiving RT after progression of BM or initial diagnosis of BM three months later. Results: Overall, 471 patients were enrolled in our study, including 260 patients receiving RT. The median follow-up time was 48 months. In entire cohort, median OS time and PFS were 15.0 and 9.0 months, respectively. In lung-molGPA0-2 group, OS of patients with or without RT was no statistical difference (HR, 0.78, 95%CI, 0.59-1.04, P= .071). While in lung-molGPA2.5-4 group, the addition of RT could prolong OS and PFS of patients (OS: HR, 0.51, 95%CI, 0.39-0.67, P&lt; .001; and PFS: HR, 0.66, 95%CI, 0.51-0.85, P&lt; .001). Moreover, in patients scored as 2.5-4.0, the median OS of early RT and delayed RT was 24.0 months and 15.0 months, respectively, and OS of patients receiving early RT was significantly superior to patients receiving delayed RT (HR, 0.50, 95%CI, 0.31-0.79, P&lt; .001). While for patients scored as 0-2, no statistical difference was between OS of patients receiving early RT and delayed RT (HR, 0.75, 95%CI, 0.51-1.10, P= .115). Conclusions: With regards as patients scored 2.5-4.0 based on lung-molGPA index, early addition of cranial radiotherapy could benefit patients’ survival. While for patients scored 0-2, the survival benefit from cranial radiotherapy was limited.
Construction and validation of the prognostic model for patients with gallbladder neuroendocrine neoplasm-based a nationwide retrospective registry study.
Authors: Xuheng Sun, Yijun WANG, Yingbin Liu
Journal: Journal of Clinical Oncology (2022)

e16140 Background: Gallbladder neuroendocrine neoplasm (GB-NEN) is an extremely rare type of gallbladder neoplasm and the prognosis of patients with GB-NENs varies widely. The focus of this study was to construct and validate a prognostic model of GB-NENs based on the data from a nationwide retrospective multicenter registry cohort. Methods: The Chinese Research Group of Gallbladder Cancer (CRGGC) study is a multicenter retrospective registry cohort study reviewing the electronic medical records from 76 tertiary and secondary hospitals across 28 provinces in China. We assembled patients with GB-NEN diagnosed between 2010 and 2017 in 24 tertiary hospitals from CRGGC study. Influential factors of recurrence free survival (RFS) and overall survival (OS) were identified using Least absolute shrinkage and selection operator (LASSO) regression and Cox predicting model was constructed for predicting RFS and OS. The prognostic model was validated both internally and externally. Performance of the model was assessed by concordance index (C-index) and calibration curves stratified by risk categories. Results: A total of 84 patients with GB-NEN was extracted from CRGGC study, among which 3 were diagnosed with GB-NEN Grade 1, 8 were diagnosed with GB-NEN Grade 2 and 35 with GB-NEN Grade 3. Of the 35 patients with GB-NEN Grade 3, 3 had poorly differentiated small-cell neuroendocrine carcinomas (SC-NECs) and 8 patients had Mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). 53 patients were included in the training group (median survival, 21.1 months; 95% confidence interval (CI), 13.8-37.6 months) and 31 patients in the validation cohort (median survival, 34.3 months; 95% CI, 9.63-58.97months). A Cox predicting model was built, including 5 variables (age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined). The C-index was 78.1 (95% CI, 63.9-92.3), with a good calibration, and these results were confirmed in the internal validation cohorts. Conclusions: We have built a clinical model for GB-NEN patients and clinical doctors for prognosis prediction based on age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined which can be easily obtained in one’s case history. It can be used to determine subgroups of patients who may have poorer prognosis and assist individualized and precise treatment for GB-NEN.
Synergistic activity of PARP inhibitors (PARPi) in combination with standard chemotherapy (CTx) in leiomyosarcoma.
Authors: Olga Vornicova, Yael Babichev, Rima Al-awar, Richard Marcellus, Albiruni Ryan Abdul Razak, Rebecca Anne Gladdy
Journal: Journal of Clinical Oncology (2022)

11560 Background: Leiomyosarcomas (LMS) are genetically heterogeneous tumors that arise from smooth muscle. Currently, the mainstay of systemic treatment for patients with advanced/metastatic disease is doxorubicin (Dox) based CTx. Several genomic analyses of LMS reveal defects in homologous recombination (HR) DNA repair pathway in about half of patients, consistent with a druggable “BRCAness” phenotype. Thus, we sought to determine which combinations of standard CTx and PARPi might be synergistic promising therapeutic strategies for LMS. Methods: Dox, Docetaxel (Doc), Temozolomide (Tmz) were evaluated in combination with PARPi (Olaparib [Ola], Niraparib [Nira] and Talazoparib [Tala]) at 12 different drug concentrations. Four LMS cell lines of different origins (gynecological - GY, abdominal - A, extremity - E) were tested in a high throughput manner. All drug concentrations were chosen according to EC 50. Cells were incubated with each combination for 7 days. Viability was assessed by ATPlite Luminescence Assay System.Evaluation of drug combination effect was performed using a Bliss synergy score. This system quantifies the degree of synergy as multiplicative effect of single drugs as if they acted independently. With a synergy score of -5 to 5, the interaction between two drugs is considered as additive; &lt;-5 antagonistic and &gt; 5 synergistic, and therefore a promising combination. Results: Anticancer activity, ranging from additive to synergistic was seen with all combinations. Results were consistent among all cell lines, independent of site of cell line origin (Table) Most synergistic combination in the majority of LMS cell lines were Dox or Tmz when combined with Tala, reaching up to 15 % and 27% above Bliss respectively. In contrast, Doc showed only additive effect with all analyzed PARPi. Conclusions: The data suggest that the combination of Dox or Tmz with PARPi may represent promising treatment options for LMS patients. Recent clinical studies support this notion in uterine LMS. Importantly these results suggest that such approach may be extended to all sites of LMS. Pre-clinical studies are underway to identify the most promising combinations for future clinical trial design. [Table: see text]
Phase 1 study of KT-333, a targeted protein degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia, and solid tumors.
Authors: Alexander Starodub, Ashwin Gollerkeri, Chris De savi, Joyoti Dey, Sagar Agarwal, Sean Donohue, Rachelle Perea, Christine Klaus, Jared Gollob
Journal: Journal of Clinical Oncology (2022)

TPS3171 Background: The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors resulting in tumor growth and promotion and hindering antitumor immunity. Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of phosphorylated STAT3 (pSTAT3). There is evidence of constitutive activation of STAT3 through genetic mutations or aberrant cellular signaling pathways in tumors such as large granular lymphocytic leukemia (LGL-L), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphomas (CTCL). Hyperactivation of STAT3 has been reported in a variety of solid tumors. In several of these cancers, the levels of pSTAT3 and/or activated STAT3 have been shown to correlate with poor clinical prognosis. As with other transcription factors, selective inhibition of STAT3 has been proven to be difficult with conventional therapeutic approaches. KT-333 is a potent highly selective, heterobifunctional small molecule degrader of STAT3. In preclinical studies, durable tumor regressions were seen with weekly KT-333 administration in STAT3-dependent T cell lymphomas, and antitumor activity was seen in solid tumors in combination with anti-PD1 (ASH 2021, SITC 2021). Methods: KT-333 is being evaluated in an open-label, dose escalation (Phase 1a, n = 40) study in patients with lymphomas relapsed or refractory (R/R) to at least two prior systemic treatments or for whom standard therapies are unavailable. Dose escalation will be conducted by accelerated titration followed by a 3+3 design in ascending doses of intravenous KT-333 administered once weekly in 28-day cycles to evaluate safety and define the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) in plasma and urine and preliminary pharmacodynamic effects (PD) of KT-333 using blood (peripheral blood mononuclear cells [PBMCs], plasma/serum) and tumor tissue. After confirming the MTD/RP2D in patients with lymphoma, patients with advanced solid tumors will be enrolled in a separate Phase 1a cohort at the MTD/RP2D. In Phase 1b (n = 80), patients with PTCL, CTCL, LGL-L (T-cell LGL-L or chronic lymphoproliferative disorder of natural killer-cells), or solid tumors R/R to at least one prior systemic standard of care treatment or for whom standard therapies are not available, will be enrolled in separate 20 patient cohorts. This will further characterize safety, PK, PD and evaluate the clinical activity of KT-333. Treatment with KT-333 will continue until disease progression, unacceptable toxicity, or patient refusal. KT333-TL-101 began enrolling in January 2022. Clinical trial information: NCT05225584.
DIPG-16. Evaluation of myeloid component of DIPG microenvironment
Authors: Deepak Mishra, Sakthi Rajendran, Xiaoting Zhu, Matthew Nazzaro, Shiva Senthil Kumar, Todd Mchugh, Prajwal Rajappa, Rachid Drissi
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable disease of the central nervous system in children with median overall survival of less than one year. In recent years, several immunotherapy strategies have emerged as an option to treat DIPG. However, the low mutational burden and rare infiltration of T lymphocytes, render these tumors immunologically “cold” and therefore pose challenges for general immunotherapy. The myeloid component was implicated in the immunosuppression in other solid tumors. Previous data have shown that DIPG tumors are enriched in macrophages, but their role in tumor growth and progression have not been elucidated. Specifically, it remains unclear whether the myeloid cells are recruited to the tumor microenvironment from the peripheral circulation. Here, we examined the recruitment of myeloid cell populations to the tumor microenvironment and further delineated their role in tumor progression in a syngeneic mouse model of DIPG. We showed that this DIPG mouse model displays an immune microenvironment similar to that of patients’ DIPGs. DIPG tumors harbored rare tumor infiltrating lymphocytes and are enriched in myeloid cells. To further characterize the phenotype and functions of these myeloid populations, we evaluated the changes in proportions of myeloid cell subsets using flow cytometry (CD11b, Ly6c, Ly6G, MHCII, F4/80, CD206, Arg1) in the bone marrow, peripheral blood, and in the tumor microenvironment during tumor progression. Also, we investigated the role of these myeloid cells in angiogenesis and immune suppression by performing histological and expression analyses of endothelial markers and chemokines (CD31, CD34, KDR, IL-10, IL-13, IL-4, CCL2, CCL5). Furthermore, decitabine (DNA methyltransferase inhibitor) treated tumors showed a decrease in myeloid population associated with a reduction in tumor growth, suggesting an important role of myeloid populations in tumor growth and progression.